Membrane for use with implantable devices

ABSTRACT

The present invention provides a biointerface membrane for use with an implantable device that interferes with the formation of a barrier cell layer including; a first domain distal to the implantable device wherein the first domain supports tissue attachment and interferes with barrier cell layer formation and a second domain proximal to the implantable device wherein the second domain is resistant to cellular attachment and is impermeable to cells. In addition, the present invention provides sensors including the biointerface membrane, implantable devices including these sensors or biointerface membranes, and methods of monitoring glucose levels in a host utilizing the analyte detection implantable device of the invention. Other implantable devices which include the biointerface membrane of the present invention, such as devices for cell transplantation, drug delivery devices, and electrical signal delivery or measuring devices are also provided.

RELATED APPLICATION

This application is a continuation of application Ser. No. 09/916,386,filed Jul. 27, 2001.

FIELD OF THE INVENTION

The present invention relates generally to biointerface membranes thatmay be utilized with implantable devices such as devices for thedetection of analyte concentrations in a biological sample, celltransplantation devices, drug delivery devices and electrical signaldelivering or measuring devices. The present invention further relatesto methods for determining analyte levels using implantable devicesincluding these membranes. More particularly, the invention relates tonovel biointerface membranes, to sensors and implantable devicesincluding these membranes, and to methods for monitoring glucose levelsin a biological fluid sample using an implantable analyte detectiondevice.

BACKGROUND OF THE INVENTION

One of the most heavily investigated analyte sensing devices is animplantable glucose sensor for detecting glucose levels in patients withdiabetes. Despite the increasing number of individuals diagnosed withdiabetes and recent advances in the field of implantable glucosemonitoring devices, currently used devices are unable to provide datasafely and reliably for long periods of time (e.g., months or years)[See, e.g., Moatti-Sirat et al., Diabetologia 35:224-30 (1992)]. Thereare two commonly used types of implantable glucose sensing devices.These types are those which are implanted intravascularly and thoseimplanted in tissue.

With reference to devices that may be implanted in tissue, adisadvantage of these devices has been that they tend to lose theirfunction after the first few days to weeks following implantation. Atleast one reason for this loss of function has been attributed to thefact that there is no direct contact with circulating blood to deliversample to the tip of the probe of the implanted device. Because of theselimitations, it has previously been difficult to obtain continuous andaccurate glucose levels. However, this information is often extremelyimportant to diabetic patients in ascertaining whether immediatecorrective action is needed in order to adequately manage their disease.

Some medical devices, including implanted analyte sensors, drug deliverydevices and cell transplantation devices require transport of solutesacross the device-tissue interface for proper function. These devicesgenerally include a membrane, herein referred to as a cell-impermeablemembrane that encases the device or a portion of the device to preventaccess by host inflammatory or immune cells to sensitive regions of thedevice.

A disadvantage of cell-impermeable membranes is that they oftenstimulate a local inflammatory response, called the foreign bodyresponse (FBR) that has long been recognized as limiting the function ofimplanted devices that require solute transport. Previous efforts toovercome this problem have been aimed at increasing localvascularization at the device-tissue interface with limited success.

The FBR has been well described in the literature and is composed ofthree main layers, as illustrated in FIG. 1. The innermost FBR layer 40,adjacent to the device, is composed generally of macrophages and foreignbody giant cells 41 (herein referred to as the barrier cell layer).These cells form a monolayer 40 of closely opposed cells over the entiresurface 48 a of a smooth or microporous (<1.0 .mu·m) membrane 48. Theintermediate FBR layer 42 (herein referred to as the fibrous zone),lying distal to the first layer with respect to the device, is a widezone (30-100 microns) composed primarily of fibroblasts 43 and fibrousmatrix 44. The outermost FBR layer 46 is loose connective granulartissue containing new blood vessels 45 (herein referred to as thevascular zone 46). A consistent feature of the innermost layers 40 and42 is that they are devoid of blood vessels. This has led to widelysupported speculation that poor transport of molecules across thedevice-tissue interface 47 is due to a lack of vascularization nearinterface 47 (Scharp et al., World J. Surg. 8:221-229 (1984), Colton andAvgoustiniatos J. Biomech. Eng. 113:152-170 (1991)).

Patents by Brauker et al. (U.S. Pat. No. 5,741,330), and Butler et al.(U.S. Pat. No. 5,913,998), describe inventions aimed at increasing thenumber of blood vessels adjacent to the implant membrane (Brauker etal.), and growing within (Butler et al.) the implant membrane at thedevice-tissue interface. The patent of Shults et al. (U.S. Pat. No.6,001,067) describes membranes that induce angiogenesis at thedevice-tissue interface of implanted glucose sensors. FIG. 2 illustratesa situation in which some blood vessels 45 are brought close to animplant membrane 48, but the primary layer 40 of cells adherent to thecell-impermeable membrane blocks glucose. This phenomenon is describedin further detail below.

In the examples of Brauker et al. (supra), and Shults et al., bilayermembranes are described that have cell impermeable layers that areporous and adhesive to cells. Cells are able to enter into theinterstices of these membranes, and form monolayers on the innermostlayer, which is aimed at preventing cell access to the interior of theimplanted device (cell impenetrable layers). Because the cellimpenetrable layers are porous, cells are able to reach pseudopodia intothe interstices of the membrane to adhere to and flatten on themembrane, as shown in FIGS. 1 and 2, thereby blocking transport ofmolecules across the membrane-tissue interface. The known art purportsto increase the local vascularization in order to increase soluteavailability. However, the present studies show that once the monolayerof cells (barrier cell layer) is established adjacent to the membrane,increasing angiogenesis is not sufficient to increase transport ofmolecules such as glucose and oxygen across the device-tissue interface.

One mechanism of inhibition of transport of solutes across thedevice-tissue interface that has not been previously discussed in theliterature is the formation of a uniform barrier to analyte transport bycells that form the innermost layer of the foreign body capsule. Thislayer of cells forms a monolayer with closely opposed cells having tightcell-to-cell junctions. When this barrier cell layer forms, it is notsubstantially overcome by increased local vascularization. Regardless ofthe level of local vascularization, the barrier cell layer prevents thepassage of molecules that cannot diffuse through the layer. Again, thisis illustrated in FIG. 2 where blood vessels 45 lie adjacent to themembrane but glucose transport is significantly reduced due to theimpermeable nature of the barrier cell layer 40. For example, bothglucose and its phosphorylated form do not readily transit the cellmembrane and consequently little glucose reaches the implant membranethrough the barrier layer cells.

It has been confirmed by the present inventors through histologicalexamination of explanted sensors that the most likely mechanism forinhibition of molecular transport across the device-tissue interface isthe barrier cell layer adjacent to the membrane. There is a strongcorrelation between desired device function and the lack of formation ofa barrier cell layer at the device-tissue interface. In the presentstudies, devices that were observed histologically to have substantialbarrier cell layers were functional only 41% of the time after 12 weeksin vivo. In contrast, devices that did not have significant barrier celllayers were functional 86% of the time after 12 weeks in vivo.

Consequently, there is a need for a membrane that interferes with theformation of a barrier layer and protects the sensitive regions of thedevice from host inflammatory response.

SUMMARY OF THE INVENTION

The biointerface membranes of the present invention interfere with theformation of a monolayer of cells adjacent to the membrane, henceforthreferred to herein as a barrier cell layer, which interferes with thetransport of oxygen and glucose across a device-tissue interface.

It is to be understood that various biointerface membrane architectures(e.g., variations of those described below) are contemplated by thepresent invention and are within the scope thereof.

In one aspect of the present invention, a biointerface membrane for usewith an implantable device is provided including; a first domain distalto the implantable device wherein the first domain supports tissueingrowth and interferes with barrier-cell layer formation and a seconddomain proximal to the implantable device wherein the second domain isresistant to cellular attachment and is impermeable to cells and cellprocesses.

In another aspect of the present invention, a biointerface membrane isprovided including the properties of: promoting tissue ingrowth into;interfering with barrier cell formation on or within; resistingbarrier-cell attachment to; and blocking cell penetration into themembrane.

In yet another aspect, a sensor head for use in an implantable device isprovided which includes a biointerface membrane of the presentinvention.

In other aspects, a sensor for use in an implantable device thatmeasures the concentration of an analyte in a biological fluid isprovided including the biointerface membrane of the present invention.

In still another aspect of the present invention, a device for measuringan analyte in a biological fluid is provided, the device including thebiointerface membrane of the present invention, a housing which includeselectronic circuitry, and at least one sensor as provided above operablyconnected to the electronic circuitry of the housing.

The present invention further provides a method of monitoring analytelevels including the steps of: providing a host, and an implantabledevice as provided above; and implanting the device in the host. In oneembodiment, the device is implanted subcutaneously.

Further provided by the present invention is a method of measuringanalyte in a biological fluid including the steps of: providing i) ahost, and ii) a implantable device as provided above capable of accuratecontinuous analyte sensing; and implanting the device in the host. Inone embodiment of the method, the device is implanted subcutaneously.

In still another aspect of the present invention, an implantable drugdelivery device is provided including a biointerface membrane asprovided above. Preferably the implantable drug delivery device is apump, a microcapsule or a macrocapsule.

The present invention further provides a device for implantation ofcells which includes a biointerface membrane as provided above.

Also encompassed by the present invention is an electrical pulsedelivering or measuring device, including a biointerface membraneaccording to that provided above.

The biointerface membranes, devices including these membranes andmethods of use of these membranes provided by the invention allow forlong term protection of implanted cells or drugs, as well as continuousinformation regarding, for example, glucose levels of a host overextended periods of time. Because of these abilities, the biointerfacemembranes of the present invention can be extremely important in themanagement of transplant patients, diabetic patients and patientsrequiring frequent drug treatment.

DEFINITIONS

In order to facilitate an understanding of the present invention, anumber of terms are defined below.

The terms “biointerface membrane,” and the like refer to a permeablemembrane that functions as a device-tissue interface comprised of two ormore domains. Preferably, the biointerface membrane is composed of twodomains. The first domain supports tissue ingrowth, interferes withbarrier cell layer formation and includes an open cell configurationhaving cavities and a solid portion. The second domain is resistant tocellular attachment and impermeable to cells (e.g., macrophages). Thebiointerface membrane is made of biostable materials and may beconstructed in layers, uniform or non-uniform gradients (i.e.anisotropic), or in a uniform or non-uniform cavity size configuration.

The term “domain” refers to regions of the biointerface membrane thatmay be layers, uniform or non-uniform gradients (e.g. anisotropic) orprovided as portions of the membrane.

The term “barrier cell layer” refers to a cohesive monolayer of closelyopposed cells (e.g. macrophages and foreign body giant cells) that mayadhere to implanted membranes and interfere with the transport ofmolecules across the membrane.

The phrase “distal to” refers to the spatial relationship betweenvarious elements in comparison to a particular point of reference. Forexample, some embodiments of a device include a biointerface membranehaving an cell disruptive domain and a cell impermeable domain. If thesensor is deemed to be the point of reference and the cell disruptivedomain is positioned farther from the sensor, then that domain is distalto the sensor.

The term “proximal to” refers to the spatial relationship betweenvarious elements in comparison to a particular point of reference. Forexample, some embodiments of a device include a biointerface membranehaving a cell disruptive domain and a cell impermeable domain. If thesensor is deemed to be the point of reference and the cell impermeabledomain is positioned nearer to the sensor, then that domain is proximalto the sensor.

The term “cell processes” and the like refers to pseudopodia of a cell.

The term “solid portions” and the like refer to a material having astructure that may or may not have an open-cell configuration, but ineither case prohibits whole cells from traveling through or residingwithin the material.

The term “substantial number” refers to the number of linear dimensionswithin a domain (e.g. pores or solid portions) in which greater than 50percent of all dimensions are of the specified size, preferably greaterthan 75 percent and, most preferably, greater than 90 percent of thedimensions have the specified size.

The term “co-continuous” and the like refers to a solid portion whereinan unbroken curved line in three dimensions exists between any twopoints of the solid portion.

The term “biostable” and the like refers to materials that arerelatively resistant to degradation by processes that are encountered invivo.

The term “sensor” refers to the component or region of a device by whichan analyte can be quantitated.

The term “analyte” refers to a substance or chemical constituent in abiological fluid (e.g., blood or urine) that is intended to be analyzed.A preferred analyte for measurement by analyte detection devicesincluding the biointerface membranes of the present invention isglucose.

The terms “operably connected,” “operably linked,” and the like refer toone or more components being linked to another component(s) in a mannerthat allows transmission of signals between the components. For example,one or more electrodes may be used to detect the amount of analyte in asample and convert that information into a signal; the signal may thenbe transmitted to an electronic circuit means. In this case, theelectrode is “operably linked” to the electronic circuitry.

The term “electronic circuitry” refers to the components of a devicerequired to process biological information obtained from a host. In thecase of an analyte measuring device, the biological information isobtained by a sensor regarding a particular analyte in a biologicalfluid, thereby providing data regarding the amount of that analyte inthe fluid. U.S. Pat. Nos. 4,757,022, 5,497,772 and 4,787,398 describesuitable electronic circuit means that may be utilized with devicesincluding the biointerface membrane of the present invention.

The phrase “member for determining the amount of glucose in a biologicalsample” refers broadly to any mechanism (e.g., enzymatic ornon-enzymatic) by which glucose can be quantitated. For example, someembodiments of the present invention utilize a membrane that containsglucose oxidase that catalyzes the conversion of oxygen and glucose tohydrogen peroxide and gluconate:Glucose+O.sub.2=Gluconate+H.sub.2O.sub.2-. Because for each glucosemolecule metabolized, there is a proportional change in the co-reactantO.sub.2 and the product H.sub.2O.sub.2, one can monitor the currentchange in either the co-reactant or the product to determine glucoseconcentration.

The term “host” refers generally to mammals, particularly humans.

The term “accurately” means, for example, 90% of measured glucose valuesare within the “A” and “B” region of a standard Clarke error grid whenthe sensor measurements are compared to a standard referencemeasurement. It is understood that like any analytical device,calibration, calibration validation and recalibration are required forthe most accurate operation of the device.

The phrase “continuous glucose sensing” refers to the period in whichmonitoring of plasma glucose concentration is continuously performed,for example, about every 10 minutes.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an illustration of classical three-layered foreign bodyresponse to a synthetic membrane implanted under the skin.

FIG. 2 is an illustration of a device having increasedneovascularization within the intermediary layer of the foreign bodyresponse.

FIG. 3 is an illustration of a membrane of the present inventionincluding a barrier-cell disruptive domain composed of fibers and a cellimpermeable domain.

FIG. 4 is an illustration of a three dimensional section of the firstdomain showing the solid portions and cavities.

FIG. 5 is an illustration of a cross-section of the first domain in FIG.4 showing solid portions and cavities.

FIG. 6A depicts a cross-sectional drawing of one embodiment of animplantable analyte measuring device for use in combination with amembrane according to the present invention.

FIG. 6B depicts a cross-sectional exploded view of the sensor head shownin FIG. 6A.

FIG. 6C depicts a cross-sectional exploded view of theelectrode-membrane region set forth in FIG. 6B.

FIG. 7 is a graphical representation of the number of functional sensorsversus time (i.e. weeks) comparing control devices including only acell-impermeable domain (“Control”), with devices including acell-impermeable domain and a barrier-cell domain, in particular,wherein the barrier-cell disruptive domain includes non-woven fiber(“Non-Woven Fibers”) and wherein the barrier-cell disruptive domainincludes porous silicone (“Porous Silicone”).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The present invention relates generally to novel biointerface membranes,their uses with implantable devices and methods for determining analytelevels in a biological fluid. More particularly, the invention providesbiointerface membranes that may be utilized with implantable devices andmethods for monitoring and determining glucose levels in a biologicalfluid, a particularly important measurement for individuals havingdiabetes.

Although the description that follows is primarily directed at glucosemonitoring devices including the biointerface membranes of the presentinvention and methods for their use, these biointerface membranes arenot limited to use in devices that measure or monitor glucose. Rather,these biointerface membranes may be applied to a variety of devices,including for example, those that detect and quantify other analytespresent in biological fluids (including, but not limited to,cholesterol, amino acids and lactate), especially those analytes thatare substrates for oxidase enzymes [see, e.g., U.S. Pat. No. 4,703,756to Gough et al., hereby incorporated by reference] cell transplantationdevices (U.S. Pat. Nos. 6,015,572, 5,964,745 and 6,083,523), drugdelivery devices (U.S. Pat. Nos. 5,458,631, 5,820,589 and 5,972,369) andelectrical delivery and/or measuring devices such as implantable pulsegeneration cardiac pacing devices (U.S. Pat. Nos. 6,157,860, 5,782,880and 5,207,218), electrocardiogram device (U.S. Pat. Nos. 4,625,730 and5,987,352) and electrical nerve stimulating devices (U.S. Pat. Nos.6,175,767, 6,055,456 and 4,940,065).

Implantable devices for detecting analyte concentrations in a biologicalsystem may utilize the biointerface membranes of the present inventionto interfere with the formation of a barrier cell layer, therebyassuring that the sensor receives analyte concentrations representativeof that in the vasculature. Drug delivery devices may utilize thebiointerface membranes of the present invention to protect the drughoused within the device from host inflammatory or immune cells thatmight potentially damage or destroy the drug. In addition, thebiointerface membrane prevents the formation of a barrier cell layerthat might interfere with proper dispensing of drug from the device fortreatment of the host. Correspondingly, cell transplantation devices mayutilize the biointerface membranes of the present invention to protectthe transplanted cells from attack by the host inflammatory or immuneresponse cells while simultaneously allowing nutrients as well as otherbiologically active molecules needed by the cells for survival todiffuse through the membrane.

The materials contemplated for use in preparing the biointerfacemembrane also eliminate or significantly delay biodegradation. This isparticularly important for devices that continuously measure analyteconcentrations. For example, in a glucose-measuring device, theelectrode surfaces of the glucose sensor are in contact with (oroperably connected with) a thin electrolyte phase, which in turn iscovered by a membrane that contains an enzyme, e.g., glucose oxidase,and a polymer system. The biointerface membrane covers this enzymemembrane and serves, in part, to protect the sensor from external forcesand factors that may result in biodegradation. By significantly delayingbiodegradation at the sensor, accurate data may be collected over longperiods of time (e.g. months to years). Correspondingly, biodegradationof the biointerface membrane of implantable cell transplantation devicesand drug delivery devices could allow host inflammatory and immune cellsto enter these devices, thereby compromising long-term function.

Devices and probes that are implanted into subcutaneous tissue willalmost always elicit a foreign body capsule (FBC) as part of the body'sresponse to the introduction of a foreign material. Therefore,implantation of a glucose sensor results in an acute inflammatoryreaction followed by building of fibrotic tissue. Ultimately, a matureFBC including primarily a vascular fibrous tissue forms around thedevice (Shanker and Greisler, Inflammation and Biomaterials in Greco RS, ed. Implantation Biology: The Host Response and Biomedical Devices,pp 68-80, CRC Press (1994)).

In general, the formation of a FBC has precluded the collection ofreliable, continuous information because it was previously believed toisolate the sensor of the implanted device in a capsule containing fluidthat did not mimic the levels of analytes (e.g. glucose and oxygen) inthe body's vasculature. Similarly, the composition of a FBC hasprevented stabilization of the implanted device, contributing to motionartifact that also renders unreliable results. Thus, conventionally, ithas been the practice of those skilled in the art to attempt to minimizeFBC formation by, for example, using a short-lived needle geometry orsensor coatings to minimize the foreign body reaction.

In contrast to conventionally known practice, the teachings of thepresent invention recognize that FBC formation is the dominant eventsurrounding long-term implantation of any sensor and must be managed tosupport rather than hinder or block sensor performance. It has beenobserved that during the early periods following implantation of ananalyte-sensing device, particularly a glucose sensing device, glucosesensors function well. However, after a few days to two or more weeks ofimplantation, these device lose their function. For example, U.S. Pat.No. 5,791,344 and Gross et al. Performance Evaluation of the MinimedContinuous Monitoring System During Patient home Use”, DiabetesTechnology and Therapuetics, Vol 2 Number 1, pp 49-56, 2000 havereported a glucose oxidase sensor (that has been approved for use inhumans by the Food and Drug Administration) that functioned well forseveral days following implantation but loses function quickly after 3days. We have observed similar device behavior with our implantablesensor. These results suggest that there is sufficient vascularizationand, therefore, perfusion of oxygen and glucose to support the functionof an implanted glucose sensor for the first few days followingimplantation. New blood vessel formation is clearly not needed for thefunction of a glucose oxidase mediated electrochemical sensor implantedin the subcutaneous tissue for at least several days after implantation.

We have observed that this lack of sensor function after several days ismost likely due to cells, such as polymorphonuclear cells and monocytesthat migrate to the wound site during the first few days afterimplantation. These cells consume glucose and oxygen. If there is anoverabundance of such cells, they may deplete the glucose and/or oxygenbefore it is able to reach the sensor enzyme layer, therefore reducingthe sensitivity of the device or rendering it non-functional. After thefirst few days, further inhibition of device function may be due tocells that associate with the membrane of the device and physicallyblock the transport of glucose into the device (i.e. barrier cells).Increased vascularization would not be expected to overcome barrier cellblockage. The present invention contemplates the use of particularbiointerface membrane architectures that interfere with barrier celllayer formation on the membrane's surface. The present invention alsocontemplates the use of these membranes with a variety of implantabledevices (e.g. analyte measuring devices, particularly glucose measuringdevices, cell transplantation devices, drug delivery devices andelectrical signal delivery and measuring devices).

The sensor interface region refers to the region of a monitoring deviceresponsible for the detection of a particular analyte. For example, insome embodiments of a glucose-monitoring device, the sensor interfacerefers to that region where a biological sample contacts (directly orafter passage through one or more membranes or layers) an enzyme (e.g.,glucose oxidase). The sensor interface region may include a biointerfacemembrane according to the present invention having different domainsand/or layers that can cover and protect an underlying enzyme membraneand the electrodes of an implantable analyte-measuring device. Ingeneral, the biointerface membranes of the present invention preventdirect contact of the biological fluid sample with the sensor. Themembranes only permit selected substances (e.g., analytes) of the fluidto pass therethrough for reaction in the immobilized enzyme domain. Thebiointerface membranes of the present invention are biostable andprevent barrier cell formation. The characteristics of this biointerfacemembrane are now discussed in more detail.

I. Biointerface Membrane

The biointerface membrane is constructed of two or more domains.Referring now to FIG. 3, preferably, the membrane includes a cellimpermeable domain 50 proximal to an implantable device, also referredto as the second domain; and a cell disruptive domain, which in theembodiment illustrated includes non-woven fibers 49 distal to animplantable device, also referred to as the first domain.

A. Barrier-Cell Disruptive (First) Domain

As described above, the outermost domain of the inventive membraneincludes a material that supports tissue ingrowth. The barrier-celldisruptive domain may be composed of an open-cell configuration havingcavities and solid portions. For example, FIG. 4 is an illustration of athree dimensional section 60 of a barrier-cell disruptive domain havingsolid portions 62 and cavities 64. Cells may enter into the cavities,however, they can not travel through or wholly exist within the solidportions. The cavities allow most substances to pass through, including,e.g., macrophages.

The open-cell configuration yields a co-continuous solid domain thatcontains greater than one cavity in three dimensions substantiallythroughout the entirety of the membrane. In addition, the cavities andcavity interconnections may be formed in layers having different cavitydimensions.

In order to better describe the dimensions of cavities and solidportions, a two dimensional plane 66 cut through the barrier-celldisruptive domain can be utilized (FIG. 5). A dimension across a cavity64 or solid portion 62 can be described as a linear line. The length ofthe linear line is the distance between two points lying at theinterface of the cavity and solid portion. In this way, a substantialnumber of the cavities are not less than 20 microns in the shortestdimension and not more than 1000 microns in the longest dimension.Preferably, a substantial number of the cavities are not less than 25microns in the shortest dimension and not more than 500 microns in thelongest dimension.

Furthermore, the solid portion has not less than 5 microns in asubstantial number of the shortest dimensions and not more than 2000microns in a substantial number of the longest dimensions. Preferably,the solid portion is not less than 10 microns in a substantial number ofthe shortest dimensions and not more than 1000 microns in a substantialnumber of the longest dimensions and, most preferably, not less than 10microns in a substantial number of the shortest dimensions and not morethan 400 microns in a substantial number of the longest dimensions.

The solid portion may be comprised of polytetrafluoroethylene orpolyethyleneco-tetrafluoroethylene. Preferably, the solid portionincludes polyurethanes or block copolymers and, most preferably, iscomprised of silicone.

In desired embodiments, the solid portion is composed of porous siliconeor non-woven fibers. Non-woven fibers are preferably made from polyesteror polypropylene. For example, FIG. 3 illustrates how the non-wovenfibers 49 serve to disrupt the continuity of cells, such that they arenot able to form a classical foreign body response. All the cell typesthat are involved in the formation of a FBR may be present. However,they are unable to form an ordered closely opposed cellular monolayerparallel to the surface of the device as in a typical foreign bodyresponse to a smooth surface. In this example, the 10-micron dimensionprovides a suitable surface for foreign body giant cells, but the fibersare in such proximity to allow and foster in growth of blood vessels 45and vascularize the biointerface region (FIG. 3). Devices with smallerfibers have been used in previous inventions, but such membranes areprone to delamination due to the forces applied by cells in theinterstices of the membrane. After delamination, cells are able to formbarrier layers on the smooth or microporous surface of the bioprotectivelayer if it is adhesive to cells or has pores of sufficient size forphysical penetration of cell processes, but not of whole cells.

When non-woven fibers are utilized as the solid portion of the presentinvention, the non-woven fibers may be greater than 5 microns in theshortest dimension. Preferably, the non-woven fibers are about 10microns in the shortest dimension and, most preferably, the non-wovenfibers are greater than or equal to 10 microns in the shortestdimension.

The non-woven fibers may be constructed of polypropylene (PP),polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polybutyleneterephthalate (PBT), polymethylmethacrylate (PMMA), polyether etherketone (PEEK), polyurethanes, cellulosic polymers, polysulfones, andblock copolymers thereof including, for example, di-block, tri-block,alternating, random and graft copolymers (block copolymers are discussedin U.S. Pat. Nos. 4,803,243 and 4,686,044, hereby incorporated byreference). Preferably, the non-woven fibers are comprised ofpolyolefins or polyester or polycarbonates or polytetrafluoroethylene.The thickness of the cell disruptive domain is not less than about 20microns and not more than about 2000 microns.

B. Cell Impermeable (Second) Domain

The inflammatory response that initiates and sustains a FBC isassociated with disadvantages in the practice of sensing analytes.Inflammation is associated with invasion of inflammatory response cells(e.g. macrophages) which have the ability to overgrow at the interfaceforming barrier cell layers which may block transport across thebiointerface membrane. These inflammatory cells may also biodegrade manyartificial biomaterials (some of which were, until recently, considerednonbiodegradable). When activated by a foreign body, tissue macrophagesdegranulate, releasing from their cytoplasmic myeloperoxidase systemhypochlorite (bleach) and other oxidative species. Hypochlorite andother oxidative species are known to break down a variety of polymers.However, polycarbonate based polyurethanes are believed to be resistantto the effects of these oxidative species and have been termedbiodurable. In addition, because hypochlorite and other oxidizingspecies are short-lived chemical species in vivo, biodegradation willnot occur if macrophages are kept a sufficient distance from the enzymeactive membrane.

The present invention contemplates the use of cell impermeablebiomaterials of a few microns thickness or more (i.e., a cellimpermeable domain) in most of its membrane architectures. Desirably,the thickness of the cell impermeable domain is not less than about 10microns and not more than about 100 microns. This domain of thebiointerface membrane is permeable to oxygen and may or may not bepermeable to glucose and is constructed of biodurable materials (e.g.for period of several years in vivo) that are impermeable by host cells(e.g. macrophages) such as, for example, polymer blends of polycarbonatebased polyurethane and PVP.

The innermost domain of the inventive membrane is non-adhesive for cells(i.e. the cell impermeable domain), which is in contrast to theinventions of Brauker et al. (supra), and Shults et al. (supra). In bothof these previous patents, examples are provided in which thecellimpenetrable membrane (Brauker et al.) or biointerface membrane(Shults et al.) are derived from a membrane known as Biopore.™. as acell culture support sold by Millipore (Bedford, Mass.). In the presenceof certain extracellular matrix molecules, and also in vivo, many celltypes are able to strongly adhere to this membrane making it incapableof serving as a non-adhesive domain. Further, since they allow adherenceof cells to the innermost layer of the membrane they promote barriercell layer formation that decreases the membranes ability to transportmolecules across the device-tissue interface. Moreover, when these cellsmultiply, they ultimately cause pressure between the membrane layersresulting in delamination of the layers and catastrophic failure of themembrane.

As described above, in one embodiment of the inventive membrane, thesecond domain is resistant to cellular attachment and is impermeable tocells and preferably composed of a biostable material. The second domainmay be formed from materials such as those previously listed for thefirst domain and as copolymers or blends with hydrophilic polymers suchas polyvinylpyrrolidone (PVP), polyhydroxyethyl methacrylate,polyvinylalcohol, polyacrylic acid, polyethers, such as polyethyleneglycol, and block copolymers thereof including, for example, di-block,tri-block, alternating, random and graft copolymers (block copolymersare discussed in U.S. Pat. Nos. 4,803,243 and 4,686,044, herebyincorporated by reference).

Preferably, the second domain is comprised of a polyurethane and ahydrophilic polymer. Desirably, the hydrophilic polymer ispolyvinylpyrrolidone. In one embodiment of this aspect of the invention,the second domain is polyurethane comprising not less than 5 weightpercent polyvinylpyrrolidone and not more than 45 weight percentpolyvinylpyrrolidone. Preferably, the second domain comprises not lessthan 20 weight percent polyvinylpyrrolidone and not more than 35 weightpercent polyvinylpyrrolidone and, most preferably, polyurethanecomprising about 27 weight percent polyvinylpyrrolidone.

As described above, in one desired embodiment the cell impermeabledomain is comprised of a polymer blend comprised of a non-biodegradablepolyurethane comprising polyvinylpyrrolidone. This prevents adhesion ofcells in vitro and in vivo and allows many molecules to freely diffusethrough the membrane. However, this domain prevents cell entry orcontact with device elements underlying the membrane, and prevents theadherence of cells, and thereby prevents the formation of a barrier celllayer.

II. Implantable Glucose Monitoring Devices Using the BiointerfaceMembranes of the Present Invention

The present invention contemplates the use of unique membranearchitectures around the sensor interface of an implantable device.However, it should be pointed out that the present invention does notrequire a device including particular electronic components (e.g.,electrodes, circuitry, etc). Indeed, the teachings of the presentinvention can be used with virtually any monitoring device suitable forimplantation (or subject to modification allowing implantation);suitable devices include, analyte measuring devices, celltransplantation devices, drug delivery devices, electrical signaldelivery and measurement devices and other devices such as thosedescribed in U.S. Pat. Nos. 4,703,756 and 4,994,167 to Shults et al.;U.S. Pat. No. 4,703,756 to Gough et al., and U.S. Pat. No. 4,431,004 toBessman et al.; the contents of each being hereby incorporated byreference, and Bindra et al., Anal. Chem. 63:1692-96 (1991).

We refer now to FIG. 6A, which shows a preferred embodiment of ananalyte measuring device for use in combination with a membraneaccording to the present invention. In this embodiment, a ceramic body 1and ceramic head 10 houses the sensor electronics that include a circuitboard 2, a microprocessor 3, a battery 4, and an antenna 5. Furthermore,the ceramic body 1 and head 10 possess a matching taper joint 6 that issealed with epoxy. The electrodes are subsequently connected to thecircuit board via a socket 8.

As indicated in detail in FIG. 6B, three electrodes protrude through theceramic head 10, a platinum working electrode 21, a platinum counterelectrode 22 and a silver/silver chloride reference electrode 20. Eachof these is hermetically brazed 26 to the ceramic head 10 and furtheraffixed with epoxy 28. The sensing region 24 is covered with the sensingmembrane described below and the ceramic head 10 contains a groove 29 sothat the membrane may be affixed into place with an o-ring.

FIG. 6C depicts a cross-sectional exploded view of theelectrode-membrane region 24 set forth in FIG. 6B detailing the sensortip and the functional membrane layers. As depicted in FIG. 6C, theelectrode-membrane region includes the inventive biointerface membrane33 and a sensing membrane 32. The top ends of the electrodes are incontact with the electrolyte phase 30, a free-flowing fluid phase. Theelectrolyte phase is covered by the sensing membrane 32 that includes anenzyme, e.g., glucose oxidase. In turn, the inventive interface membrane33 covers the enzyme membrane 32 and serves, in part, to protect thesensor from external forces that may result in environmental stresscracking of the sensing membrane 32.

III. Experimental

The following examples serve to illustrate certain preferred embodimentsand aspects of the present invention and are not to be construed aslimiting the scope thereof

In the preceding description and the experimental disclosure whichfollows, the following abbreviations apply: Eq and Eqs (equivalents);mEq (milliequivalents); M (molar); mM (millimolar) .mu·M (micromolar); N(Normal); mol (moles); mmol (millimoles); .mu·mol (micromoles); nmol(nanomoles); g (grams); mg (milligrams); .mu·g (micrograms); Kg(kilograms); L (liters); mL (milliliters); dL (deciliters); .mu·L(microliters); cm (centimeters); mm (millimeters); .mu·m (micrometers);nm (nanometers); h and hr (hours); min. (minutes); s and sec. (seconds);.degree. C. (degrees Centigrade); Astor Wax (Titusville, Pa.); BASFWyandotte Corporation (Parsippany, N.J.); Data Sciences, Inc. (St. Paul,Minn.); Douglas Hansen Co., Inc. (Minneapolis, Minn.); DuPont (DuPontCo., Wilmington, Del.); Exxon Chemical (Houston, Tex.); GAF Corporation(New York, N.Y.); Markwell Medical (Racine, Wis.); Meadox Medical, Inc.(Oakland, N.J.); Mobay (Mobay Corporation, Pittsburgh, Pa.); Sandoz(East Hanover, N.J.); and Union Carbide (Union Carbide Corporation;Chicago, Ill.).

Example 1 Preparation of Biointerface Membrane with Non-Woven Fibers

The barrier-cell disruptive domain may be prepared from a non-wovenpolyester fiber filtration membrane. The cell-impermeable domain maythen be coated on this domain layer. The cell-impermeable domain wasprepared by placing approximately 706 gm of dimethylacetamide (DMAC)into a 3 L stainless steel bowl to which a polycarbonateurethanesolution (1325 g, Chronoflex AR 25% solids in DMAC and a viscosity of5100 cp) and polyvinylpyrrolidone (125 g, Plasdone K-90D) were added.The bowl was then fitted to a planetary mixer with a paddle type bladeand the contents were stirred for 1 hour at room temperature. Thissolution was then coated on the barrier-cell disruptive domain byknife-edge drawn at a gap of 0.006″ and dried at 60.degree. C. for 24hours. The membrane is then mechanically secured to the sensing deviceby an O-ring.

Example 2 Preparation of Biointerface Membrane with Porous Silicone

The barrier-cell disruptive domain can be comprised of a porous siliconesheet. The porous silicone was purchased from Seare Biomatrix Systems,Inc. The cell-impermeable domain was prepared by placing approximately706 gm of dimethylacetamide (DMAC) into a 3 L stainless steel bowl towhich a polycarbonateurethane solution (1,325 gm, Chronoflex AR 25%solids in DMAC and a viscosity of 5100 cp) and polyvinylpyrrolidone (125gm, Plasdone K-90D) were added. The bowl was then fitted to a planetarymixer with a paddle type blade and the contents were stirred for 1 hourat room temperature. The cell-impermeable domain coating solution wasthen coated onto a PET release liner (Douglas Hansen Co.) using a knifeover roll set at a 0.012″ gap. This film was then dried at 305.degree.F. The final film was approximately 0.0015″ thick. The biointerfacemembrane was prepared by pressing the porous silicone onto the castcell-impermeable domain. The membrane is then mechanically secured tothe sensing device by an O-ring.

Example 3 Test Method for Glucose Measuring Device Function

In vivo sensor function was determined by correlating the sensor outputto blood glucose values derived from an external blood glucose meter. Wehave found that non-diabetic dogs do not experience rapid blood glucosechanges, even after ingestion of a high sugar meal. Thus, a 10% dextrosesolution was infused into the sensor-implanted dog. A second catheter isplaced in the opposite leg for the purpose of blood collection. Theimplanted sensor was programmed to transmit at 30-second intervals usinga pulsed electromagnet. A dextrose solution was infused at a rate of 9.3ml/minute for the first 25 minutes, 3.5 ml/minute for the next 20minutes, 1.5 ml/minute for the next 20 minutes, and then the infusionpump was powered off Blood glucose values were measured in duplicateevery five minutes on a blood glucose meter (LXN Inc., San Diego,Calif.) for the duration of the study. A computer collected the sensoroutput. The data was then compiled and graphed in a spreadsheet, timealigned, and time shifted until an optimal R-squared value was achieved.The R-squared value reflects how well the sensor tracks with the bloodglucose values.

Example 4 In Vivo Evaluation of Glucose Measuring Devices Including theBiointerface Membranes of the Present Invention

To test the importance of a cell-disruptive membrane, implantableglucose sensors comprising the biointerface membranes of the presentinvention were implanted into dogs in the subcutaneous tissues andmonitored for glucose response on a weekly basis. Control devicescomprising only a cell-impermeable domain (“Control”) were compared withdevices comprising a cell-impermeable domain and a barrier-celldisruptive domain, in particular, wherein the barrier-cell disruptivedomain was either a non-woven fiber (“Non-Woven Fibers”) or poroussilicone (“Porous Silicone”).

Four devices from each condition were implanted subcutaneously in theventral abdomen of normal dogs. On a weekly basis, the dogs were infusedwith glucose as described in Example 3 in order to increase their bloodglucose levels from about 120 mg/dl to about 300 mg/dl. Blood glucosevalues were determined with a LXN blood glucose meter at 5-minuteintervals. Sensor values were transmitted at 0.5-minute intervals.Regression analysis was done between blood glucose values and thenearest sensor value within one minute. Devices that yielded anR-squared value greater than 0.5 were considered functional. FIG. 7shows, for each condition, the number of functional devices over the12-week period of the study. Both test devices performed better than thecontrol devices over the first 9 weeks of the study. All of the poroussilicone devices were functional by week 9. Two of 4 polypropylene fiberdevices were functional by week 2, and 3 of 4 were functional on week12. In contrast, none of the control devices were functional until week10, after which 2 were functional for the remaining 3 weeks. These dataclearly show that the use of a cell-disruptive layer in combination witha cell-impermeable layer improves the function of implantable glucosesensors.

The description and experimental materials presented above are intendedto be illustrative of the present invention while not limiting the scopethereof It will be apparent to those skilled in the art that variationsand modifications can be made without departing from the spirit andscope of the present invention.

1. A biointerface membrane, the membrane comprising: a first domain,wherein the first domain comprises a solid portion having a plurality ofinterconnected cavities therein that form an architecture that supportstissue in ingrowth and interferes with barrier cell layer formation,wherein the solid portion comprises silicone; and a second domain,wherein the second domain is permeable to the passage of an analyte andis impermeable to cells or cell processes.
 2. The biointerface membraneaccording to claim 1, wherein the cavities form a cavernousconfiguration with greater than one cavity in three dimensionssubstantially throughout the entirety of the first domain.
 3. Thebiointerface membrane according to claim 2, wherein the cavities areformed in a plurality of layers, each layer having different cavitydimensions.
 4. The biointerface membrane according to claim 1, wherein asubstantial number of the cavities are from about 20 microns to about2000 microns in at least one dimension.
 5. The biointerface membraneaccording to claim 1, wherein a substantial number of the cavities arefrom about 25 microns to about 1000 microns in at least one dimension.6. The biointerface membrane according to claim 1, wherein the seconddomain comprises a biostable material.
 7. The biointerface membraneaccording to claim 6, wherein the biostable material comprises ahydrophobic portion and a hydrophilic portion.
 8. The biointerfacemembrane according to claim 6, wherein the biostable material comprisespolyurethane.
 9. The biointerface membrane according to claim 6, whereinthe biostable material comprises polyurethane and a hydrophilic polymer.10. The biointerface membrane according to claim 6, wherein thebiostable material comprises polyurethane and polyvinylpyrrolidone. 11.The biointerface membrane according to claim 6, wherein the bio stablematerial comprises silicone and a hydrophilic component.
 12. Thebiointerface membrane according to claim 6, wherein the biostablematerial comprises silicone and polyethylene glycol.
 13. An implantabledevice, the device comprising a biointerface membrane, the membranecomprising a first domain and a second domain, wherein the first domainis distal to the implantable device, wherein the first domain comprisesa solid portion comprising silicone and having a plurality ofinterconnected cavities therein that form a cavernous configuration withgreater than one cavity in three dimensions substantially throughout theentirety of the first domain, wherein the second domain is proximal tothe implantable device, and wherein the second domain is permeable tothe passage of a chemical and is impermeable to cells or cell processes.14. The implantable device of claim 13, comprising an analyte sensor.15. The implantable device of claim 13, comprising a glucose sensor. 16.The implantable device of claim 13, comprising a cell transplantationdevice.
 17. The implantable device of claim 13, comprising a drugdelivery device.
 18. The implantable device of claim 17, wherein thedrug delivery device is selected from the group consisting of a pump, amicrocapsule, and a macrocapsule.
 19. The implantable device of claim13, comprising an electrical signal measuring device.
 20. Theimplantable device of claim 13, comprising an electrical pulsedelivering device.
 21. A method of monitoring an analyte level, themethod comprising: implanting an implantable analyte sensor in a host,the sensor comprising a biointerface membrane, the membrane comprising afirst domain and a second domain, wherein the first domain is distal tothe implantable device, wherein the first domain comprises a solidportion comprising silicone and having a plurality of interconnectedcavities therein that form an architecture that supports tissue ingrowthand interferes with barrier cell layer formation, wherein the seconddomain is proximal to the implantable device, and wherein the seconddomain is permeable to the passage of an analyte and is impermeable tocells or cell processes; and monitoring an analyte level.
 22. The methodaccording to claim 21, wherein implanting the sensor in the hostcomprises implanting the sensor in a subcutaneous tissue of a host. 23.The method according to claim 21, wherein the analyte sensor isconfigured to permit accurate continuous analyte sensing.
 24. The methodaccording to claim 21, wherein implanting the sensor in the hostcomprises implanting the sensor in a subcutaneous tissue of a host. 25.An implantable device, the device comprising: a membrane, the membranecomprising a biointerface region comprising a cavernous first portionand a non-cavernous second portion, wherein the non-cavernous secondportion is resistant to cellular attachment, cells, or cell processes,and wherein the non-cavernous second portion is permeable to the passageof at least one chemical, wherein the cavernous first portion comprisesa plurality of interconnected cavities and has greater than one cavityin three dimensions substantially throughout the entirety of thecavernous first portion.
 26. The implantable device according to claim25, wherein the cavernous first portion comprises a solid portion formedwith the plurality of interconnected cavities therein and configured tosupport tissue ingrowth and interfere with barrier cell layer formation.27. The implantable device according to claim 25, wherein a substantialnumber of the cavities are from about 20 microns to about 2000 micronsin at least one dimension.
 28. The implantable device according to claim25, wherein a substantial number of the cavities are from about 25microns to about 1000 microns in at least one dimension.
 29. Theimplantable device according to claim 25, wherein the cavities areformed in a plurality of layers, each layer having different cavitydimensions.
 30. The implantable device according to claim 25, whereinthe second portion comprises a biostable material.
 31. The implantabledevice according to claim 30, wherein the biostable material comprises ahydrophobic portion and a hydrophilic portion.
 32. The implantabledevice according to claim 30, wherein the biostable material comprisespolyurethane.
 33. The implantable device according to claim 30, whereinthe biostable material comprises polyurethane and a hydrophilic polymer.34. The implantable device according to claim 30, wherein the biostablematerial comprises polyurethane and polyvinylpyrrolidone.
 35. Theimplantable device according to claim 30, wherein the biostable materialcomprises silicone and a hydrophilic component.
 36. The implantabledevice according to claim 30, wherein the first portion comprisessilicone.
 37. The implantable device according to claim 25, wherein thedevice comprises an implantable glucose sensor.
 38. The implantabledevice according to claim 25, wherein the device comprises a celltransplantation device.
 39. The implantable device according to claim25, wherein the device comprises a drug delivery device.
 40. Theimplantable device according to claim 39, wherein the drug deliverydevice is selected from the group consisting of a pump, a microcapsule,and a macrocapsule.
 41. The implantable device according to claim 25,wherein the device comprises an electrical signal measuring device. 42.The implantable device according to claim 25, wherein the devicecomprises an electrical pulse delivering device.
 43. An implantableglucose sensor, the sensor comprising: a porous silicone portion; anon-porous skin, wherein the non-porous skin is adjacent to the poroussilicone portion, and wherein the non-porous skin is permeable toglucose and is impermeable to cells or cell processes; and a glucosemeasuring device.
 44. An implantable sensor, the sensor comprising: aporous membrane comprising silicone and configured to allow cells andcell processes to pass through; a non-porous membrane that is permeableto analytes and impermeable to cells and cell processes; and an analytemeasuring device.
 45. An implantable glucose sensor, the sensorcomprising: a fibrous domain that supports tissue ingrowth andconfigured to allow cells and cell processes to pass through; anon-fibrous domain, wherein the non-fibrous domain is adjacent to thefibrous domain, and wherein the non-fibrous domain is permeable toanalytes and is impermeable to cells or cell processes; and a glucosemeasuring device.